The Invariant Peptide Clusters of Serum Amyloid A Are Humoral Checkpoints for Vital Innate Functions as Probed by Monoclonal Antibodies, Including in Sepsis: Induction by Febrile Temperatures and Path of Discoveries

Serum amyloid A (SAA) is the most prominent acute-phase protein in vertebrates and its role in innate immunity has been reviewed. SAA functions are located on special regions of SAA, which are highly conserved in all vertebrates. 1. The discovery of the acute-phase nature of SAA before its existence was known by experimental murine AA amyloidosis induced by septic conditions. 2. Identification of the amyloid substance and its precursor. 3. SAA changes its conformation and antigenic presentation when it is separated from HDL during the acute phase. Febrile temperatures activate SAA through the separation from HDL. There is a temperature-specific gradual separation of SAA isotypes or groups of isotypes from HDL. 4. Generic monoclonal AA antibodies mc4 and mc29 assist in elucidating selected SAAs’ vital functions (as in defense, platelet functions, female propagation and others). 5. In a murine sepsis model, the monoclonals mc4 and mc29 can cause early death while the intact SAA can prevent this. Through this, a checkpoint (“stop and go”) for survival was discovered. Generic monoclonals can also identify the life-saving structures of SAA’s vital functions and those of other acute-phase proteins. This principle is essential for the production of novel drugs against sepsis and other innate-related diseases. 6. Some remarks follow

Hepatic acute-phase proteins control innate immune responses during infection by promoting myeloid-derived suppressor cell function

Acute-phase proteins (APPs) are an evolutionarily conserved family of proteins produced mainly in the liver in response to infection and inflammation. Despite vast pro- and antiinflammatory properties ascribed to individual APPs, their collective function during infections remains poorly defined. Using a mouse model of polymicrobial sepsis, we show that abrogation of APP production by hepatocyte-specific gp130 deletion, the signaling receptor shared by IL-6 family cytokines, strongly increased mortality despite normal bacterial clearance. Hepatic gp130 signaling through STAT3 was required to control systemic inflammation. Notably, hepatic gp130–STAT3 activation was also essential for mobilization and tissue accumulation of myeloid-derived suppressor cells (MDSCs), a cell population mainly known for antiinflammatory properties in cancer. MDSCs were critical to regulate innate inflammation, and their adoptive transfer efficiently protected gp130-deficient mice from sepsis-associated mortality. The hepatic APPs serum amyloid A and Cxcl1/KC cooperatively promoted MDSC mobilization, accumulation, and survival, and reversed dysregulated inflammation and restored survival of gp130-deficient mice. Thus, gp130-dependent communication between the liver and MDSCs through APPs controls inflammatory responses during infection

Cathepsin K as a novel amyloid fibril protein in humans

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